ABSTRACT ?-synuclein expression, c-Abl activation, and neuronal glutathione levels are each recognized as contributory factors in Parkinson?s disease, but how these factors interact is poorly understood. This knowledge gap is of basic and therapeutic relevance because these interactions may define a final common pathway in Parkinson?s disease pathogenesis. Glutathione is used by neurons to both scavenge reactive oxygen species and repair oxidatively damage proteins. In Parkinson?s disease, the accumulation of ?- synuclein oligomers is associated with glutathione depletion, oxidative stress, and neuronal death. ?-synuclein aggregate formation is promoted by c-Abl, a tyrosine kinase that is in turn activated by oxidative stress. We hypothesize that ?-synuclein aggregates drive reactive oxygen species formation through metal-catalyzed processes, and that the resulting glutathione depletion contributes to ?-synuclein aggregation and c-Abl activation in a feed-forward manner. We will test this hypothesis using cell culture models in which ?- synuclein aggregates, thiol redox state, and c-Abl activity can be independently manipulated and monitored. We will also employ two novel double-transgenic mouse strains that permit evaluation of a-synuclein aggregation and its associated pathology in the setting of (1) deficient NADPH oxidase activity, and (2) reduced neuronal glutathione levels. These strains, in combination with novel pharmacological tools, will allow us to identify cause- effect relationships between neuronal oxidative stress, ?-synuclein aggregation, and c-Abl activity in vivo. 1